1. Field
Provided is a conjugate including a c-Met targeting compound and a bioactive material and methods of use of the conjugate.
2. Description of the Related Art
c-Met is a hepatocyte growth factor (HGF) receptor, encoded by the oncogene c-met, functioning to mediate a wide spectrum of signals driven by its ligand HGF which binds to an extracellular domain of the c-Met receptor tyrosine kinase to induce the promotion of division, motility, morphogenesis and angiogenesis in various normal and cancer cells. In some cases, c-Met is involved, irrespective of its ligand HGF, in a variety of tumorigenesis including oncogenesis, metastasis, cancer cell migration, cancer cell invasion, and angiogenesis, therefore attracting a keen interest as a target protein for cancer therapy.
Particularly, c-Met is recognized as being of significance for personalized therapy as it is known to play a role in drug resistance with regard to the activity of conventional anticancer agents. Erbitux and Tarceva, both representative anticancer agents which target EGFR (ERBB1), perform their functions by blocking oncogenic mechanism-related signal transduction. Herceptin, a typical therapeutic for breast cancer, functions to block a signal pathway necessary for cell growth, targeting ERBB2 (HER2). However, recent studies on patients with resistance to the drugs reported that other signaling pathways responsible for cell growth are activated by detouring the action of the anticancer agents through the overexpression of c-Met. For this reason, c-Met is a target molecule to which many pharmaceutical companies pay keen attention, attempting to develop various drugs, for example, antibodies, which are designed to bind to c-Met to inhibit HGF signaling.
These c-Met targeting drugs are known to exhibit anticancer efficiency in various c-Met positive cancers. On the contrary, some c-Met targeting drugs (for example, antibodies) are observed to act as an agonist causative of the side effect (agonism) that they combine by themselves to induce the dimerization of c-Met, irrespective of the ligand, thereby initiating oncogenic signaling. In addition, another problem is the impotence of c-Met targeting drugs (for example, antibodies) in cancer cells which express the antigen c-Met at a low level. An antibody-drug conjugate (ADC) was also developed in which an antibody is conjugated with a drug was developed to synergize the targeting of the drug, but is disadvantageously ineffective in internalization.